IgE antibodies mediate allergic and asthmatic reactions, characterized by immediate hypersensitivity and an inflammatory delayed-type responses requiring the recruitment of effector cells. IgE antibodies are transported from the peripheral circulation into tissues, where they can bind allergic effector cells such as mast cells, basophils, eosinophils, dendritic cells, Langerhans cells, monocytes, and macrophages via three types of Fc receptors: FcεRI (or high-affinity FcεR) (Ka=1011M−1), FcεRII (or low-affinity FcεR, CD23) (Ka<108 M−1), and galectin-3. Unlike antibodies of the IgG class, IgE binds to its FcR with extremely high affinity, which in the case of FcεRI is about three orders of magnitude higher than that of IgG for the FcRs (FcγRI-III) and in the case of FcεRII is as high as that of IgG for its high affinity FcγRI (Gould, H J, et al., Annu. Rev. Immunol., 21: 579-628. (2003); Gounni, A S, et al., Nature, 367: 183-186 (1994); Kinet, J P, Annu. Rev. Immunol., 17: 931-72:931-972 (1999) and Ravetch J V, and Kinet J P, Annu. Rev. Immunol., 9: 457-492 (1991)).
The newly arising field of AllergoOncology is based upon observations and studies suggesting an inverse correlation between IgE-mediated allergy and cancer (Turner M C, et al., Int. J. Cancer, 118: 3124-3132 (2006); Wang H & Diepgen T L, Allergy 60: 1098-1111, (2005); Turner M C, et al., Am. J. Epidemiol., 162: 212-221 (2005); Wang H, et al., Int. J. Cancer, 119: 695-701 (2006); Mills P K, et al., Am. J. Epidemiol., 136: 287-295 (1992); Wiemels J L, et al., Cancer Res., 64: 8468-8473 (2004); Dodig S., et al., Acta Pharm., 55: 123-138 (2005); and Wrensch M., et al., Cancer Res., 66: 4531-4541 (2006)). As a result, researchers in this field are exploring the therapeutic potential of the IgE antibody class in the prevention and treatment of certain cancers, under the premise that immune responses originally developed as adaptive responses to microbial/parasitic infection might be useful when directed against malignancy.
The application of IgE for the therapy of cancer was pioneered by Nagy et al. (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)), who developed a murine IgE monoclonal antibody specific for the major envelope glycoprotein (gp36) of mouse mammary tumor virus (MMTV) and demonstrated significant anti-tumor activity in C3H/HeJ mice bearing a syngeneic MMTV-secreting mammary adenocarcinoma (H2712) (Nagy, E., et al., Cancer Immunol. Immunother., 34: 63-69 (1991)). Kershaw et al. (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)) developed a murine monoclonal IgE named 30.6, specific for an antigenic determinant expressed on the surface of colorectal adenocarcinoma cells. Mouse IgE 30.6 inhibited the growth of established human colorectal carcinoma COLO 205 cells growing subcutaneously in severe combined immune deficient (SCID) mice, although this effect was transient. By contrast, a mouse IgG 30.6 did not show anti-tumor effects. The mouse IgE specific effect was attributed to the interaction of the antibody with FcεR bearing effector cells since the activity was specifically abrogated by prior administration of a nonspecific mouse IgE (Kershaw, M H, et al., Oncol. Res., 10: 133-142 (1998)). Gould et al. developed a mouse/human chimeric IgE (MOv18-IgE) and IgG MOv18 (IgG1) specific for the ovarian cancer tumor-associated antigen folate binding protein (FBP). The protective activities of MOv18-IgE and MOv18-IgG1 were compared in a SCID mouse xenograft model of human ovarian carcinoma (IGROV1). The beneficial effects of MOv18-IgE were greater and of longer duration than those of MOv18-IgG1 demonstrating the superior anti-tumor effects of IgE antibodies (Gould, H J, et al., Eur. J. Immunol., 29: 3527-3537 (1999)).
Recently Karagiannis et al. demonstrated monocyte-mediated IgE-dependent tumor cell killing by two distinct pathways, ADCC (antibody-dependent cell-mediated cytotoxicity) and ADCP (antibody-dependent cell-mediated phagocytosis), mediated through FcεRI and FcεRII (Karagiannis, S N, et al., Cancer Immunol. Immunother., 57: 247-263 (2008) and Karagiannis, S N, et al., J. Immunol., 179: 2832-2843 (2007)). This group also used this assay system to demonstrate that anti-Her2 IgE can activate monocytes to kill tumor cells in vitro via ADCC (Karragiannis P., et al., Cancer Immunol. Immunother., 58: 915-930 (2009) Published on-line 22 Oct. 2008). Additional examples include Fu, et al. (Clin. Exp. Immunol., 153:401-409, 2008) who demonstrated that antibodies of the IgE class isolated from pancreatic cancer patients mediate ADCC against cancer cells, and Spillner et al. (Cancer Immunol. Immunother., 61: 1565-1573 (2012) who showed using monocytes, that cytotoxicity against the human epithelial carcinoma cell line A431 was increased up to 95% with anti-EGFR IgE when compared with anti-EGFR IgG in vitro.
In spite of the encouraging findings in the emerging field of AllergoOncology, a strong need continues for the development of novel therapeutics in the treatment of metastatic cancer.